Tse Ka-Po, Su Wen-Hui, Chang Kai-Ping, Tsang Ngan-Ming, Yu Chia-Jung, Tang Petrus, See Lee-Chu, Hsueh Chuen, Yang Min-Lee, Hao Sheng-Po, Li Hong-Yi, Wang Ming-Hsi, Liao Li-Ping, Chen Lih-Chyang, Lin Sheue-Rong, Jorgensen Timothy J, Chang Yu-Sun, Shugart Yin Yao
Genomic Medicine Core, Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
Am J Hum Genet. 2009 Aug;85(2):194-203. doi: 10.1016/j.ajhg.2009.07.007. Epub 2009 Aug 6.
Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; p(combined) = 3.9 x 10(-20) and 1.6 x 10(-19), respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; p(combined) = 8.97 x 10(-17)) and HLA-F (rs3129055 and rs9258122; p(combined) = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p < 5 x 10(-4)) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA(B) receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.
鼻咽癌（NPC）是一种与遗传因素和爱泼斯坦-巴尔病毒感染密切相关的多因素恶性肿瘤。为了确定与NPC易感性相关的常见基因变异，我们在台湾人群中的277例NPC患者和285例健康对照中进行了全基因组关联研究（GWAS），分析了480,365个单核苷酸多态性（SNP）。鉴定出12个具有统计学意义的SNP，并将其定位到6号染色体p21.3区域。在两组独立的病例对照样本中重复了这些关联。两个最显著的SNP（rs2517713和rs2975042；合并p值分别为3.9×10^(-20)和1.6×10^(-19)）位于HLA-A基因中。此外，我们检测到NPC与两个基因之间存在显著关联：具体而言，γ-氨基丁酸b受体1（GABBR1）（rs29232；合并p值=8.97×10^(-17)）和HLA-F（rs3129055和rs9258122；合并p值分别为7.36×10^(-11)和3.33×10^(-1))。值得注意的是，在调整年龄、性别和HLA相关SNP后，rs29232的关联仍然显著（剩余p值<5×10^(-/)）。此外，与NPC活检中的相邻上皮细胞相比，肿瘤细胞中可发现更高的GABA(B)受体1表达水平（p<0.001），这意味着GABBR1在NPC致癌过程中具有生物学作用。据我们所知，这是第一篇关于NPC的GWAS报告，表明6号染色体p21.3区域内的多个位点（HLA-A、HLA-F和GABBR1）与NPC相关。尽管其中一些关系可能归因于位点之间的连锁不平衡，但这些发现显然为NPC发展的研究提供了一个新的方向。
